Evidence is presented to show that rifampicin causes mutations in Escherichia coli and Salmonella typhimurium. Our preliminary results strongly implicate RNA polymerase being part of this novel mutagenic pathway. This conclusion is reinforced by the fact that many rifampicin-resistant mutants are mutagenic. We have isolated several rifampicin-resistant RNA polymerase mutators that revert point or framshift mutations at high frequency. The mechanism of RNA polymerase mediated mutagenesis is totally unknown. Three models are proposed to account for this phenomenon. First, RNA polymerase could control mutation rates by its interaction with the DNA replication complex. Alternatively, altered RNA polymerase could be mutagenic by turning on other wise silent DNA repair pathways. Finally, transcriptional errors caused by altered RNA polymerase could lead to the production of altered DNA replication and repair proteins which are mutagenic. Genetic analysis will be carried out to examine the interaction between RNA polymerase mutators and proteins in the replication complex such as DNA polymerase I, DNA polymerase III and DNA gyrase. The mutator activity in rec A and uvr background will be examined to determine if RNA polymerase mutators function by inducing the post-replication or the excision repair pathways. Finally, RNA polymerase from wild-type and mutator strains will be purified to compare their transcriptional fidelity in vitro.